Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen & Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Psychopharmacology (Berl). 2012 Aug;222(4):565-77. doi: 10.1007/s00213-012-2651-y. Epub 2012 Feb 25.
Several studies suggest a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. However, the NPY receptors mediating addiction-related effects remain to be determined.
To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural effects.
The Y5 antagonist L-152,804 and Y5-knockout (Y5-KO) mice were tested in two models of cocaine addiction-related behaviour: acute self-administration and cocaine-induced hyperactivity. We also studied effects of Y5 receptor antagonism on cocaine-induced c-fos expression and extracellular dopamine with microdialysis as well as dopamine transporter-mediated uptake of dopamine in vitro. Immunocytochemistry was used to determine whether dopamine neurons express Y5-like immunoreactivity.
In self-administration, L-152,804 prominently decreased nose-poking for the peak dose of cocaine and shifted the dose-response curve for cocaine downward. Y5-KO mice also showed modestly attenuated self-administration. Cocaine-induced hyperactivity was attenuated by L-152,804 and in Y5-KO mice. Cocaine failed to increase c-fos expression in the nucleus accumbens and striatum of L-152,804-treated mice, indicating that the Y5 antagonist could act by influencing neural activity in these regions. Accordingly, the cocaine-induced increase in accumbal extracellular dopamine was attenuated by L-152,804 and in Y5-KO mice, suggesting that Y5 antagonism influences cocaine-induced behaviour by regulating dopamine. Consistent with this concept, dopamine neurons in the ventral tegmental area appeared to contain Y5 receptors. In contrast, neither L-152,804 nor NPY influenced dopamine transporter-mediated dopamine uptake.
The present data indicate that Y5 antagonism may attenuate cocaine-induced behavioural effects, suggesting that Y5 receptors could be a potential therapeutic target in cocaine addiction.
几项研究表明，神经肽 Y（NPY）在包括可卡因在内的滥用药物成瘾中起作用。然而，介导成瘾相关效应的 NPY 受体仍有待确定。
探索 Y5 NPY 受体在可卡因诱导的行为效应中的潜在作用。
使用 Y5 拮抗剂 L-152,804 和 Y5 敲除（Y5-KO）小鼠测试两种可卡因成瘾相关行为模型：急性自我给药和可卡因诱导的过度活动。我们还研究了 Y5 受体拮抗作用对可卡因诱导的 c-fos 表达和细胞外多巴胺的影响，以及使用微透析和体外多巴胺转运体介导的多巴胺摄取来研究多巴胺。免疫细胞化学用于确定多巴胺神经元是否表达 Y5 样免疫反应性。
在自我给药中，L-152,804 明显减少了可卡因峰值剂量的鼻戳，并将可卡因的剂量-反应曲线向下转移。Y5-KO 小鼠的自我给药也表现出适度减弱。L-152,804 和 Y5-KO 小鼠均减弱了可卡因诱导的过度活动。可卡因未能增加 L-152,804 处理小鼠伏隔核和纹状体中的 c-fos 表达，表明 Y5 拮抗剂可以通过影响这些区域的神经活动来发挥作用。相应地，L-152,804 和 Y5-KO 小鼠中的可卡因诱导的伏隔核细胞外多巴胺增加减弱，表明 Y5 拮抗作用通过调节多巴胺来影响可卡因诱导的行为。与这一概念一致，腹侧被盖区的多巴胺神经元似乎含有 Y5 受体。相比之下，L-152,804 和 NPY 均不影响多巴胺转运体介导的多巴胺摄取。
本研究数据表明，Y5 拮抗作用可能减弱可卡因诱导的行为效应，表明 Y5 受体可能成为可卡因成瘾的潜在治疗靶点。
